Past investigations have established the major events in thyroid system ontogenesis during the fetal-neonatal period in developing mammals. The maturation of neuro-endocrine control and regulatory aspects of thyroid hormone production and the development of tissue responsiveness to thyroid hormones are the last steps in this ontogenesis. The proposed studies employ the fetal and newborn lamb and fetal-neonatal mouse for detailed investigations of these aspects of hypothalamic-pituitary-thyroid system maturation and function during development. We will study the development of neuroendocrine control of hypothalamic thyrotropin releasing hormone (TRH) and pituitary thyrotropin (TSH) secretion; the significance of hypothalamic and extrahypothalamic TRH in fetal metabolism and thyroid development; the maturation of pituitary TRH and triiodothyronine (T3) receptor systems; the ontogenesis of thyroid TSH receptors; the maturation of liver, lung, heart and brain thyroid hormone nuclear receptors, including receptor specificity; the development of liver and kidney mitochondrial T3 receptors; the correlation of thyroid system receptor maturation ad hormone responses; the role of nerve growth factor (NGF) and epidermal growth factor (EGF) in the maturation of hypothalamic-pituitary function; and the interrelationships of thyroid hormones and EGF in skin maturation. The results will help clarify the mechanism(s) of the immaturities on thyroid system function in premature infants as well as the significance of these thyroid dysfunction syndromes, and will provide basic information regarding the timing and the mechanism(s) of thyroid hormone stimulation of growth and development which will be important in the management of hypothyroidism in the fetus and newborn.